• Temporal stability and prognostic biomarker potential of the prostate cancer urine transcriptome

      Jeon, J; Olkhov-Mitsel, E; Xie, H; Yao, CQ; Zhao, F; Jahangiri, S; Cuizon, C; Scarcello, S; Jeyapala, R; Watson, JD; et al. (2019)
      BACKGROUND: To provide rapid evaluation of patients with advanced urological malignancies, a joint urological-oncological clinic was initiated at our institution in January 2015. We present the first 3-year evaluation of this joint urological-oncological clinic in Switzerland. METHOD: We performed a retrospective analysis of the characteristics and treatment of all patients reviewed at the joint clinic between January 2015 and December 2017. Statistical analysis was performed by survival analysis. A patient satisfaction questionnaire was handed out to new patients (from April to September 2017). RESULTS: A total of 135 new patients were counseled in the joint clinic and 563 consultations were performed in the period from January 2015 to December 2017. The majority were men with prostate cancer (85%), followed by bladder cancer (9%), and renal cell carcinoma (4%). Men with newly diagnosed metastatic prostate cancer (n = 69) received ADT alone (57%), ADT with docetaxel or abiraterone (33%), and metastasis-directed therapy (10%). High rates of patient satisfaction were reported based on the questionnaire. CONCLUSIONS: The joint clinic model has been successfully implemented at our institution and continues on a weekly basis. The clinic is increasingly used, not only for newly diagnosed metastatic prostate cancer, but also for other complex uro-oncological cases. The clinic allows optimized oncological treatment without delay and with a reduced effort for patients.
    • Cysteine cathepsin protease inhibition: an update on its diagnostic, prognostic and therapeutic potential in cancer

      Soond, SM; Kozhevnikova, MV; Townsend, Paul A; Zamyatnin, AA; Institute of Molecular Medicine, Sechenov First Moscow State Medical University, Trubetskaya str. 8-2, 119991 Moscow, Russia. (2019)
      In keeping with recent developments in basic research; the importance of the Cathepsins as targets in cancer therapy have taken on increasing importance and given rise to a number of key areas of interest in the clinical setting. In keeping with driving basic research in this area in a translational direction; recent findings have given rise to a number of exciting developments in the areas of cancer diagnosis; prognosis and therapeutic development. As a fast-moving area of research; the focus of this review brings together the latest findings and highlights the translational significance of these developments.
    • Letter to the editor in response to 'When to apply sunscreen: a consensus statement for Australia and New Zealand'

      Baldwin, L; Olsen, CM; Gordon, L; Green, Adele C; Aitken, J; Neale, R; Whiteman, D; Janda, M; Institute of Health and Biomedical Research, School of Public Health and Social Work, Faculty of Health, Queensland University of Technology, Australia (2019)
    • Frailty in older patients undergoing emergency laparotomy: results from the UK observational Emergency Laparotomy and Frailty (ELF) study

      Parmar, Kat; Law, J; Carter, B; Hewitt, J; Boyle, JM; Casey, P; Maitra, I; Farrell, IS; Pearce, L; Moug, SJ; et al. (2019)
      OBJECTIVE: This study aimed to document the prevalence of frailty in older adults undergoing emergency laparotomy and to explore relationships between frailty and postoperative morbidity and mortality. SUMMARY BACKGROUND DATA: The majority of adults undergoing emergency laparotomy are older adults (³65 y) that carry the highest mortality. Improved understanding is urgently needed to allow development of targeted interventions. METHODS: An observational multicenter (n=49) UK study was performed (March-June 2017). All older adults undergoing emergency laparotomy were included. Preoperative frailty score was calculated using the progressive Clinical Frailty Score (CFS): 1 (very fit) to 7 (severely frail). Primary outcome measures were the prevalence of frailty (CFS 5-7) and its association to mortality at 90 days postoperative. Secondary outcomes included 30-day mortality and morbidity, length of critical care, and overall hospital stay. RESULTS: A total of 937 older adults underwent emergency laparotomy: frailty was present in 20%. Ninety-day mortality was 19.5%. After age and sex adjustment, the risk of 90-day mortality was directly associated with frailty: CFS 5 adjusted odds ratio (aOR) 3.18 [95% confidence interval (CI), 1.24-8.14] and CFS 6/7 aOR 6á10 (95% CI, 2.26-16.45) compared with CFS 1. Similar associations were found for 30-day mortality. Increasing frailty was also associated with increased risk of complications, length of Intensive Care Unit, and overall hospital stay. CONCLUSIONS: A fifth of older adults undergoing emergency laparotomy are frail. The presence of frailty is associated with greater risks of postoperative mortality and morbidity and is independent of age. Frailty scoring should be integrated into acute surgical assessment practice to aid decision-making and development of novel postoperative strategies.
    • Author correction: Molecular subtypes of small cell lung cancer: a synthesis of human and mouse model data

      Rudin, CM; Poirier, JT; Byers, LA; Dive, Caroline; Dowlati, A; George, J; Heymach, JV; Johnson, JE; Lehman, JM; MacPherson, D; et al. (2019)
      An amendment to this paper has been published and can be accessed via a link at the top of the paper. Erratum for Molecular subtypes of small cell lung cancer: a synthesis of human and mouse model data. [Nat Rev Cancer. 2019]
    • Phenotype plasticity as enabler of melanoma progression and therapy resistance

      Arozarena, I; Wellbrock, Claudia; Navarrabiomed, Complejo Hospitalario de Navarra (CHN), Universidad Publica de Navarra (UPNA), Instituto de Investigacion Sanitaria de Navarra (IdiSNA), Pamplona, Spain (2019)
      Malignant melanoma is notorious for its inter- and intratumour heterogeneity, based on transcriptionally distinct melanoma cell phenotypes. It is thought that these distinct phenotypes are plastic in nature and that their transcriptional reprogramming enables heterogeneous tumours both to undergo different stages of melanoma progression and to adjust to drug exposure during treatment. Recent advances in genomic technologies and the rapidly expanding availability of large gene expression datasets have allowed for a refined definition of the gene signatures that characterize these phenotypes and have revealed that phenotype plasticity plays a major role in the resistance to both targeted therapy and immunotherapy. In this Review we discuss the definition of melanoma phenotypes through particular transcriptional states and reveal the prognostic relevance of the related gene expression signatures. We review how the establishment of phenotypes is controlled and which roles phenotype plasticity plays in melanoma development and therapy. Because phenotype plasticity in melanoma bears a great resemblance to epithelial-mesenchymal transition, the lessons learned from melanoma will also benefit our understanding of other cancer types.
    • Risk of melanoma recurrence After diagnosis of a high-risk primary tumor

      von Schuckmann, LA; Hughes, MCB; Ghiasvand, R; Malt, M; van der Pols, JC; Beesley, VL; Khosrotehrani, K; Smithers, BM; Green, Adele C; Population Health Department, QIMR Berghofer Medical Research Institute, Brisbane, Australia (2019)
      Importance: With emerging new systemic treatments for metastatic melanoma, early detection of disease recurrence is increasingly important. Objective: To investigate the risk of melanoma recurrence in patients with a localized melanoma at a high risk of metastasis. Design, Setting, and Participants: A total of 1254 patients with newly diagnosed, histologically confirmed tumor category T1b to T4b melanoma in Queensland, Australia, were recruited prospectively between October 1, 2010, and October 1, 2014, for participation in a cohort study. Data analysis was conducted from February 8, 2018, to February 20, 2019. We used Cox proportional hazards regression analysis to examine associations between patient and tumor factors and melanoma recurrence. Exposures: Disease-free survival (DFS) by melanoma tumor category defined by the 7th vs 8th editions of the AJCC Cancer Staging Manual (AJCC 7 vs AJCC 8). Main Outcomes and Measures: Melanoma recurrences were self-reported through follow-up questionnaires administered every 6 months and confirmed by histologic or imaging findings. Results: Of 1254 patients recruited, 825 individuals (65.8%) agreed to participate. Thirty-six were found to be ineligible after providing consent and a further 89 patients were excluded after reclassifying tumors using AJCC 8, leaving 700 participants with high-risk primary melanoma (mean [SD] age, 62.2 [13.5] years; 410 [58.6%] men). Independent predictors of recurrence were head or neck site of primary tumor, ulceration, thickness, and mitotic rate greater than 3/mm2 (hazard ratio, 2.36; 95% CI, 1.19-4.71). Ninety-four patients (13.4%) developed a recurrence within 2 years of diagnosis: 66 tumors (70.2%) were locoregional, and 28 tumors (29.8%) developed at distant sites. After surgery for locoregional disease, 37 of 64 patients (57.8%) remained disease free at 2 years, 7 patients (10.9%) developed new locoregional recurrence, and 20 patients (31.3%), developed distant disease. Two-year DFS was similar when comparing AJCC 7 and AJCC 8, for T1b (AJCC 7, 253 [93.3% DFS]; AJCC 8, 242 [93.0% DFS]) and T4b (AJCC 7 and AJCC 8, 50 [68.0% DFS] category tumors in both editions. Patients with T2a to T4a tumors who did not have a sentinel lymph node biopsy (SLNB) at diagnosis had lower DFS than patients with the same tumor category and a negative SLNB (T2a: 136 [91.1%; 95% CI, 86.4-95.9] vs 96 [96.9%; 95 % CI, 93.4-100.0]; T4a: 33 [78.8%; 95% CI, 64.8-92.7] vs 6 [83.3; 95% CI, 53.5-100.0]). Conclusions and Relevance: These findings suggest that 13.4% of patients with a high-risk primary melanoma will experience disease recurrence within 2 years. Head or neck location of initial tumor, SLNB positivity, and signs of rapid tumor growth may be associated with primary melanoma recurrence.
    • Optical coherence tomography to detect acute esophageal radiation-induced damage in mice: a validation study

      Jelvehgaran, P; de Bruin, DM; Khmelinskii, A; Borst, G; Steinberg, JD; Song, JY; de Vos, J; van Leeuwen, TG; Alderliesten, T; de Boer, JF; et al. (2019)
      Radiation therapy for patients with non-small-cell lung cancer is hampered by acute radiation-induced toxicity in the esophagus. This study aims to validate that optical coherence tomography (OCT), a minimally invasive imaging technique with high resolution (~10 ?m), is able to visualize and monitor acute radiation-induced esophageal damage (ARIED) in mice. We compare our findings with histopathology as the gold standard. Irradiated mice receive a single dose of 40 Gy at proximal and distal spots of the esophagus of 10.0 mm in diameter. We scan mice using OCT at two, three, and seven days post-irradiation. In OCT analysis we define ARIED as a presence of distorted esophageal layering, change in backscattering signal properties, or change in the esophageal wall thickness. The average esophageal wall thickness is 0.53 mm larger on OCT when ARIED is present based on histopathology. The overall sensitivity and specificity of OCT to detect ARIED compared to histopathology are 94 % and 47 %, respectively. However, the overall sensitivity of OCT to assess ARIED is 100% seven days post-irradiation. We validated the capability of OCT to detect ARIED induced by high doses in mice. Nevertheless, clinical studies are required to assess the potential role of OCT to visualize ARIED in humans. This article is protected by copyright. All rights reserved.
    • Histologic features associated with an invasive component in lentigo maligna lesions

      Moreno, A; Manrique-Silva, E; Viros, Amaya; Requena, C; Sanmartin, O; Traves, V; Nagore, E; School of Medicine, Universidad Catolica de Valencia San Vicente Martir, Valencia, Spain (2019)
      Importance: Lentigo maligna (LM) presents an invasive component in up to 20% of biopsied cases, but to date the histologic features useful in detecting this invasive component have not been described. Some histologic characteristics are hypothesized to contribute to the progression of LM invasion. Objective: To identify the histologic characteristics associated with lentigo maligna melanoma (LMM) in patients with LM diagnosed by a partial diagnostic biopsy. Design, Setting, and Participants: A retrospective cross-sectional study of patients treated between January 1, 2000, and December 31, 2017, was conducted in a referral oncology center in València, Spain. Data and specimens of patients (n?=?96) with a diagnosis of primary cutaneous melanoma in the form of either LM or LMM who had undergone surgical treatment, a complete histologic examination of the whole tumor, and an initial diagnostic partial biopsy of LM were included in the study. Histologic assessment was blinded to the presence of an invasive component. Interventions: All biopsy specimens were evaluated for the presence of certain histologic characteristics. Main Outcomes and Measures: Comparisons between invasive samples and samples without an invasive component were performed. The differences in the distribution of variables between the groups were assessed using the ?2 and Fisher exact tests, and the degree of association of the relevant variables was quantified by logistic regression models. A classification and regression tree analysis was performed to rank the variables by importance. Results: In total, 96 patients had sufficient histologic material that could be evaluated. The patients were predominantly male (56 [58.3%]) and had a mean (SD) age at diagnosis of 72 (12) years. Of these patients, 63 (65.6%) had an LM diagnosis and 33 (34.4%) had an LMM diagnosis (an invasive component). The histologic variables associated with the presence of an invasive component were melanocytes forming rows (odds ratio [OR], 11.5; 95% CI, 1.4-94.1; P?=?.02), subepidermal clefts (OR, 2.8; 95% CI, 1.0-7.9; P?=?.049), nests (OR, 3.0; 95% CI, 1.1-8.6; P?=?.04), and a lesser degree of solar elastosis (OR, 0.4; 95% CI, 0.1-1.1; P?=?.07). A classification and regression tree analysis of the relevant histologic features was able to accurately identify lentigo maligna with an invasive component (LMM) in more than 60% of patients. Conclusions and Relevance: These findings may be useful in classifying early LM specimens at higher risk of invasion, which may eventually be relevant in identifying the most appropriate management for LM.
    • Hypoxia and angiogenic biomarkers in prostate cancer after external beam radiotherapy (EBRT) alone or combined with high-dose-rate brachytherapy boost (HDR-BTb)

      Bhattacharya, IS; Taghavi, Azar SM; Alonzi, R; Hoskin, Peter J; Institute of Cancer Research Clinical Trials and Statistics Unit (ICR-CTSU), London, United Kingdom (2019)
      PURPOSE: To investigate angiogenic and hypoxia biomarkers to predict outcome in patients receiving external beam radiotherapy (EBRT) alone or combined with high-dose-rate brachytherapy boost (HDR-BTb) for localised prostate cancer. METHODS: Prostate biopsy samples were collected prospectively in patients entered into a phase 3 randomised controlled trial of patients receiving EBRT or EBRT?+?HDR-BTb. Univariate and multivariate analyses using Cox proportional hazards model were performed to identify associations between immunohistochemical staining of hypoxia inducible factor 1 alpha (HIF1?), glucose transporter 1 (GLUT1), osteopontin (OPN) and microvessel density (MVD) using CD-34 antibody with clinical outcome. The primary endpoint was biochemical relapse free survival (BRFS) and secondary endpoint was distant metastasis free survival (DMFS). RESULTS: Immunohistochemistry was available for 204 patients. Increased OPN (Hazard ratio [HR] 2.38, 95% Confidence Interval [CI] 1.06-5.34, p?<?0.036) and GLUT1 (HR 2.36, 95%CI 1.39-4.01, p?<?0.001) expression were predictive of worse BRFS. Increased GLUT1 expression (HR 2.22, 1.02-4.84, p?=?0.045) was predictive of worse DMFS. Increased MVD (CD-34) (HR 1.82, 95%CI 1.06-3.14, p?=?0.03) and OPN (HR 1.82, 95%CI 1.06-3.14, p?=?0.03) but reduced GLUT1 expression (HR 0.40, 95%CI 0.20-0.79, p?=?0.009) were predictive of improved BRFS in patients receiving EBRT?+?HDR-BTb. CONCLUSION: Our data suggest angiogenic and hypoxia biomarkers may predict outcome and benefit of dose escalation, however further validation in prospective studies including hypoxia modification is needed. Trial registration number ISRCTN98241100, registered with ISRCTN at http://www.controlled-trials.com/isrctn/.
    • Hypoxia-induced secretion stimulates breast cancer stem cell regulatory signalling pathways

      Jacobsson, H; Harrison, Hannah; Hughes, E; Persson, E; Rhost, S; Fitzpatrick, P; Gustafsson, A; Andersson, D; Gregersson, P; Magnusson, Y; et al. (2019)
      It is well known that tumor cells are dependent on communication with the tumor microenvironment. Previously, it has been shown that hypoxia induces pronounced, diverse and direct effects on cancer stem cell (CSC) qualities in different breast cancer subtypes. Here, we describe the mechanism by which hypoxia-induced secretion influence CSC spreading. Conditioned media from estrogen receptor (ER)-? positive hypoxic breast cancer cell cultures increased the fraction of CSCs compared to normal growth conditions, as determined using sets of CSC assays and model systems. In contrast, media from ER?-negative hypoxic cell cultures instead decreased this key subpopulation of cancer cells. Further, there was a striking overrepresentation of JAK-STAT-associated cytokines in both the ER?-positive and ER?-negative linked hypoxic responses as determined by a protein screen of the conditioned media. JAK-STAT inhibitors and knockdown experiments further supported the hypothesis that this pathway is critical for the CSC activating and inactivating effects induced by hypoxic secretion. We also observed that the interleukin (IL)-6 -JAK2-STAT3 axis was specifically central for the ER?-negative hypoxic behaviour. Our results underline the importance of considering breast cancer subtypes in treatments targeting JAK-STAT or hypoxia-associated processes, and indicate that hypoxia is not only a confined tumor biological event, but also influences key tumor properties in widespread normoxic microenvironments. This article is protected by copyright. All rights reserved.
    • Asymmetric inheritance of cell fate determinants: focus on RNA

      Shlyakhtina, Yelyzaveta; Moran, Katherine L; Portal, Maximiliano M; Cell Plasticity & Epigenetics Lab, Cancer Research UK(-)Manchester Institute, The University of Manchester, SK10 4TG Manchester, UK. (2019)
      During the last decade, and mainly primed by major developments in high-throughput sequencing technologies, the catalogue of RNA molecules harbouring regulatory functions has increased at a steady pace. Current evidence indicates that hundreds of mammalian RNAs have regulatory roles at several levels, including transcription, translation/post-translation, chromatin structure, and nuclear architecture, thus suggesting that RNA molecules are indeed mighty controllers in the flow of biological information. Therefore, it is logical to suggest that there must exist a series of molecular systems that safeguard the faithful inheritance of RNA content throughout cell division and that those mechanisms must be tightly controlled to ensure the successful segregation of key molecules to the progeny. Interestingly, whilst a handful of integral components of mammalian cells seem to follow a general pattern of asymmetric inheritance throughout division, the fate of RNA molecules largely remains a mystery. Herein, we will discuss current concepts of asymmetric inheritance in a wide range of systems, including prions, proteins, and finally RNA molecules, to assess overall the biological impact of RNA inheritance in cellular plasticity and evolutionary fitness.
    • In silico prediction of housekeeping long intergenic non-coding RNAs reveals HKlincR1 as an essential player in lung cancer cell survival

      Memon, Danish; Bi, J; Miller, Crispin J; RNA Biology Group, CRUK Manchester Institute, The University of Manchester, Alderley Park, Manchester, SK10 4TG, (2019)
      Prioritising long intergenic noncoding RNAs (lincRNAs) for functional characterisation is a significant challenge. Here we applied computational approaches to discover lincRNAs expected to play a critical housekeeping (HK) role within the cell. Using the Illumina Human BodyMap RNA sequencing dataset as a starting point, we first identified lincRNAs ubiquitously expressed across a panel of human tissues. This list was then further refined by reference to conservation score, secondary structure and promoter DNA methylation status. Finally, we used tumour expression and copy number data to identify lincRNAs rarely downregulated or deleted in multiple tumour types. The resulting list of candidate essential lincRNAs was then subjected to co-expression analyses using independent data from ENCODE and The Cancer Genome Atlas (TCGA). This identified a substantial subset with a predicted role in DNA replication and cell cycle regulation. One of these, HKlincR1, was selected for further characterisation. Depletion of HKlincR1 affected cell growth in multiple lung cancer cell lines, and led to disruption of genes involved in cell growth and viability. In addition, HKlincR1 expression was correlated with overall survival in lung adenocarcinoma patients. Our in silico studies therefore reveal a set of housekeeping noncoding RNAs of interest both in terms of their role in normal homeostasis, and their relevance in tumour growth and maintenance.
    • Association between dietary patterns and keratinocyte cancers in organ transplant recipients

      Shao, E; Miura, K; Green, Adele C; Faculty of Medicine, University of Queensland, Brisbane,Queensland, Australia (2019)
    • Melanoma incidence in Australian commercial pilots, 2011-2016

      Olsen, CM; Miura, K; Dusingize, JC; Hosegood, I; Brown, R; Drane, M; Clem, P; Marsden, J; Tinker, R; Karipidis, K; et al. (2019)
      OBJECTIVES: Occupational exposure to cosmic and ultraviolet radiation may increase airline pilots' risk of cutaneous melanoma. Meta-analyses of available data show a higher than average incidence of melanoma in airline pilots, but the most recent systematic review revealed that few contemporary data are available. Moreover, all relevant studies have been conducted in Northern Hemisphere populations. We therefore aimed to examine if Australian commercial pilots have a raised incidence of melanoma compared with the general population. METHODS: We examined all melanoma histologically diagnosed among Australian-licensed commercial pilots in the period 2011-2016 by manually reviewing de-identified data in the medical records system of the Australian Civil Aviation Safety Authority. We estimated age-specific incidence rates and compared these with corresponding population rates using standardised incidence ratios (SIRs) as measures of relative risk. Expected numbers were calculated by multiplying age- and calendar period-specific person-years (PYs) with corresponding rates from the entire Australian population; 95% CI were calculated assuming a Poisson distribution of the observed cases. RESULTS: In this cohort of Australian-licensed commercial pilots observed for 91 370 PYs, 114 developed a melanoma (51 invasive, 63 in situ). More than 50% of melanomas occurred on the trunk, and the predominant subtype was superficial spreading melanoma. The SIR for invasive melanoma was 1.20 (95% CI 0.89 to 1.55) and for melanoma in situ, 1.39 (95% CI 1.08 to 1.78). CONCLUSION: Australian-licensed commercial pilots have a modestly raised risk of in situ melanoma but no elevation of invasive melanoma compared with the general population.
    • Clinicopathological factors associated with death from thin (<= 1 mm) melanoma

      Claeson, M; Baade, P; Brown, S; Soyer, P; Smithers, M; Green, Adele C; Whiteman, D; Khosrotehrani, K; Department of Population Health, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia (2019)
    • Pre-clinical investigations of CAR T cells directed against the tumour antigen 5T4 (OXB-302) in solid tumor models

      Kelleher, M; Harrop, R; Blount, D; Gilham, David E; Cheadle, Eleanor J; Edmondson, R; Owens, Gemma L; Oxford BioMedica UK Ltd, Translat Sci Grp, Oxford (2019)
    • FKBPL and its peptide derivatives inhibit endocrine therapy resistant cancer stem cells and breast cancer metastasis by downregulating DLL4 and Notch4

      McClements, L; Annett, S; Yakkundi, A; O'Rourke, M; Valentine, A; Moustafa, N; Alqudah, A; Simoes, Bruno M; Furlong, F; Short, A; et al. (2019)
      BACKGROUND: Optimising breast cancer treatment remains a challenge. Resistance to therapy is a major problem in both ER- and ER+ breast cancer. Tumour recurrence after chemotherapy and/or targeted therapy leads to more aggressive tumours with enhanced metastatic ability. Self-renewing cancer stem cells (CSCs) have been implicated in treatment resistance, recurrence and the development of metastatic disease. METHODS: In this study, we utilised in vitro, in vivo and ex vivo breast cancer models using ER+ MCF-7 and ER- MDA-MB-231 cells, as well as solid and metastatic breast cancer patient samples, to interrogate the effects of FKBPL and its peptide therapeutics on metastasis, endocrine therapy resistant CSCs and DLL4 and Notch4 expression. The effects of FKBPL overexpression or peptide treatment were assessed using a t-test or one-way ANOVA with Dunnett's multiple comparison test. RESULTS: We demonstrated that FKBPL overexpression or treatment with FKBPL-based therapeutics (AD-01, pre-clinical peptide /ALM201, clinical peptide) inhibit i) CSCs in both ER+ and ER- breast cancer, ii) cancer metastasis in a triple negative breast cancer metastasis model and iii) endocrine therapy resistant CSCs in ER+ breast cancer, via modulation of the DLL4 and Notch4 protein and/or mRNA expression. AD-01 was effective at reducing triple negative MDA-MB-231 breast cancer cell migration (n???3, p?<?0.05) and invasion (n???3, p?<?0.001) and this was translated in vivo where AD-01 inhibited breast cancer metastasis in MDA-MB-231-lucD3H1 in vivo model (p?<?0.05). In ER+ MCF-7 cells and primary breast tumour samples, we demonstrated that ALM201 inhibits endocrine therapy resistant mammospheres, representative of CSC content (n???3, p?<?0.05). Whilst an in vivo limiting dilution assay, using SCID mice, demonstrated that ALM201 alone or in combination with tamoxifen was very effective at delaying tumour recurrence by 12 (p?<?0.05) or 21?days (p?<?0.001), respectively, by reducing the number of CSCs. The potential mechanism of action, in addition to CD44, involves downregulation of DLL4 and Notch4. CONCLUSION: This study demonstrates, for the first time, the pre-clinical activity of novel systemic anti-cancer therapeutic peptides, ALM201 and AD-01, in the metastatic setting, and highlights their impact on endocrine therapy resistant CSCs; both areas of unmet clinical need. KEYWORDS: AD-01; ALM201; Breast cancer stem cells; DLL4; Endocrine therapy; Estrogen receptor; FKBPL; Letrozole; Metastasis; Notch4; Tamoxifen; Triple negative breast cancer
    • Low perfusion compartments in glioblastoma quantified by advanced magnetic resonance imaging and correlated with patient survival

      Li, C; Yan, JL; Torheim, Turid; McLean, MA; Boonzaier, NR; Zou, J; Huang, Y; Yuan, J; van Dijken, BRJ; Matys, T; et al. (2019)
      BACKGROUND AND PURPOSE: Glioblastoma exhibits profound intratumoral heterogeneity in perfusion. Particularly, low perfusion may induce treatment resistance. Thus, imaging approaches that define low perfusion compartments are crucial for clinical management. MATERIALS AND METHODS: A total of 112 newly diagnosed glioblastoma patients were prospectively recruited for maximal safe resection. The apparent diffusion coefficient (ADC) and relative cerebral blood volume (rCBV) were calculated from diffusion and perfusion imaging, respectively. Based on the overlapping regions of lowest rCBV quartile (rCBVL) with the lowest ADC quartile (ADCL) and highest ADC quartile (ADCH) in each tumor, two low perfusion compartments (ADCH-rCBVL and ADCL-rCBVL) were identified for volumetric analysis. Lactate and macromolecule/lipid levels were determined from multivoxel MR spectroscopic imaging. Progression-free survival (PFS) and overall survival (OS) were analyzed using Kaplan-Meier's and multivariate Cox regression analyses, to evaluate the effects of compartment volume and lactate level on survival. RESULTS: Two compartments displayed higher lactate and macromolecule/lipid levels compared to contralateral normal-appearing white matter (each P?<?0.001). The proportion of the ADCL-rCBVL compartment in the contrast-enhancing tumor was associated with a larger infiltration on FLAIR (P?<?0.001, rho?=?0.42). The minimally invasive phenotype displayed a lower proportion of the ADCL-rCBVL compartment than the localized (P?=?0.031) and diffuse phenotypes (not significant). Multivariate Cox regression showed higher lactate level in the ADCL-rCBVL compartment was associated with worsened survival (PFS: HR 2.995, P?=?0.047; OS: HR 4.974, P?=?0.005). CONCLUSIONS: Our results suggest that the ADCL-rCBVL compartment may potentially indicate a clinically measurable resistant compartment.
    • Decoding the interdependence of multiparametric magnetic resonance imaging to reveal patient subgroups correlated with survivals

      Li, C; Wang, S; Liu, P; Torheim, Turid; Boonzaier, NR; van Dijken, BR; Schonlieb, CB; Markowetz, F; Price, SJ; Cambridge Brain Tumor Imaging Laboratory, Division of Neurosurgery, Department of Clinical Neurosciences, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK (2019)
      Glioblastoma is highly heterogeneous in microstructure and vasculature, creating various tumor microenvironments among patients, which may lead to different phenotypes. The purpose was to interrogate the interdependence of microstructure and vasculature using perfusion and diffusion imaging and to investigate the utility of this approach in tumor invasiveness assessment. A total of 115 primary glioblastoma patients were prospectively recruited for preoperative magnetic resonance imaging (MRI) and surgery. Apparent diffusion coefficient (ADC) was calculated from diffusion imaging, and relative cerebral blood volume (rCBV) was calculated from perfusion imaging. The empirical copula transform was applied to ADC and rCBV voxels in the contrast-enhancing tumor region to obtain their joint distribution, which was discretized to extract second-order features for an unsupervised hierarchical clustering. The lactate levels of patient subgroups, measured by MR spectroscopy, were compared. Survivals were analyzed using Kaplan-Meier and multivariate Cox regression analyses. The results showed that three patient subgroups were identified by the unsupervised clustering. These subtypes showed no significant differences in clinical characteristics but were significantly different in lactate level and patient survivals. Specifically, the subtype demonstrating high interdependence of ADC and rCBV displayed a higher lactate level than the other two subtypes (P?=?.016 and P?=?.044, respectively). Both subtypes of low and high interdependence showed worse progression-free survival than the intermediate (P?=?.046 and P?=?.009 respectively). Our results suggest that the interdependence between perfusion and diffusion imaging may be useful in stratifying patients and evaluating tumor invasiveness, providing overall measure of tumor microenvironment using multiparametric MRI.